The concept of inhibiting exocrine pancreatic secretion to prevent postoperative complications after pancreatic surgery originated in 1979, with Klempa and colleagues;30
they reported lower complication rates after a perioperative continuous infusion of somatostatin (250 mg/h) in patients who underwent a Whipple procedure. The synthetic somatostatin analogue, octreotide (SMS 201–995) is more favourable for clinical use because it possesses a longer half-life.32
Many surgeons now routinely administer perioperative octreotide to patients undergoing elective pancreatic resection.
The focus of this meta-analysis was to address the following controversial question: Is perioperative octreotide effective in reducing the incidence of pancreatic fistula and death after elective pancreatic resection?
Pancreatic fistula remains a challenging problem after pancreatic surgery. It is the most frequent complication after pancreatic resection, occurring in 5% to 35%15–19
of patients. Activated exocrine pancreatic secretion is thought to be a main etiological factor. It has been reported that the mortality after pancreatic surgery is between 3% and 10%.4,9,10,14
Our literature review identified 7 studies that were eligible for this meta-analysis: 4 European multicentre randomized, controlled double-blinded trails, 2 American RCTs and 1 French study.35,37,39,41–43,45
The 4 European studies directly opposed the results of the 2 American studies. Each of the 4 European trials reported a lower incidence of pancreatic fistula in the octreotide group. These trials were performed in many centres by many different surgeons, which might explain the high rate of pancreatic fistula in each of their placebo groups (19%–37%). This contrasts with the American studies, which were done in specialized centres with high-volume experienced surgeons. The rate of pancreatic fistula in the placebo group ranged from 6% to 9%. This low incidence cannot be explained by octreotide administration alone. The surgeon's experience, the type of anastomosis and the quality of the tissue are important determinants.
The definition of a pancreatic fistula is very important. In this meta-analysis, we defined pancreatic fistula as a postoperative drain output of fluid, with an amylase content of more than 3 times the serum level, exceeding 10 mL per 24 hours for more than 3 days; this biochemical leak is more liberal and is adopted by European studies. Yeo and colleagues45
adopted a more conservative definition (> 50 mL after postoperative day 10). They considered biochemical leak to be unimportant, because the most leaks resolve without squelae. Lowy and colleagues41
separated both leaks. The clinical leak rate was 12% in the octreotide group, versus 6% in the placebo group, whereas the total leak rate (clinical and biochemical) was 28% in the octreotide group versus 21% in the control group. The discrepancy in the rate of pancreatic fistula between the European and American trials may partially a result of the inclusion of more biochemical leaks in the early trials.
In the European studies, patients were stratified into 2 groups: high-risk patients (soft pancreas, nonpancreatic and periampullary tumours) and low-risk patients (fibrotic pancreas, chronic pancreatitis). The low-risk group of patients had more favourable pancreatic tissue with which to create an anastomosis, due to the fibrosis of the gland, a larger pancreatic duct and, perhaps, a reduced overall pancreatic exocrine function.
Lowy and colleagues41
reported a single-centre trial at the University of Texas MD Anderson Cancer Center in Houston, Texas. All 120 patients underwent pancreaticoduodenectomy, with use of a standard operative technique. The rate of pancreatic fistula was 6% in the control group and 12% in the octreotide group. This study has received some criticism, because 46 of 110 patients received preoperative chemoradiation, and 64 of 110 patients received intraoperative radiation; this could have resulted in a lower complication rate.41
Yeo and colleagues45
at Johns Hopkins Hospital, Baltimore, studied 211 patients undergoing pancreaticoduodenectomy. The rate of pancreatic fistula was 9% in the control group and 11% in the octreotide group. They concluded that prophylactic octreotide has no benefit and should be eliminated at a considerable cost savings.
Octreotide is a well-tolerated drug with few side effects. The main side effect is pain at the injection site. Buchler and others35,36
reported 31 of 125 patients with this problem; however, it did not require discontinuation of the treatment. Other side effects include hot flashes, rash, fever, nausea, emesis and asymptomatic biliary sludge. No major systemic side effects, such as glucose imbalance, were encountered in any of these studies.35,37,41–43,45
Factors influencing the risk of pancreatic fistula development after pancreatic surgery include the type of surgery (Whipple v. distal pancreatectomy), consistency of the gland and, most importantly, the surgeon's experience. Lerut and colleagues55
described the influence of age, preoperative renal insufficiency and emergency surgery, whereas Yeo and colleagues45
described a strong association between the texture of the gland and fistula formation, with a higher fistula rate in soft-texture glands.
The type of surgery could influence the rate of pancreatic fistula development. Montorsi and colleagues42
found no statistical difference in the rate of pancreatic fistula in patients who underwent pancreaticoduodenectomy; this was supported by the findings of Yeo and colleagues45
and Lowy and colleagues.41
On the contrary, pancreatic fistula was significantly lower in the octreotide group than in the placebo group for patients who underwent distal pancreatectomy and local pancreatic resection, when combined together.
The pooled analysis of these 1359 patients — 679 in the octreotide group and 680 in the control group — showed that prophylactic octreotide is associated with a significant reduction of postoperative pancreatic fistula. Further research is warranted to define subgroups of patients who may benefit most from octreotide administration.